Approach to a child with chronic diarrhea

Riccardo Troncone
 Definitions

Diarrhea
>200 ml/m2/day
>150-200 g/m2/day

Chronic diarrhea
Decrease of consistency and/or increase of
frequency and/or volume of stools lasting longer
than two weeks, where the change in stool
consistency is more important than stool frequency
 Mechanisms
(more than one may be implicated)
Osmotic diarrhea
Non absorbed substances reaching the distal bowel increase
osmotic charge thus pulling water along the intestinal lumen

Secretory diarrhea
Increased active secretion of water and electrolytes into the
intestinal lumen surpassing the absorptive capability

Inflammatory diarrhea
Enterocyte injury with inflammatory response, impaired intestinal
permeability

Motility alterations
Hypermotility or hypomotility
Main mechanisms for diarrhoea
 History
•Age
•Modalities of beginning
•Family history
•Growth
•Associated symptoms
•Dietary history
•Stool characteristics
 Diseases characterized by chronic diarrhea
according to the age at beginning
0-30 days 2-24 months 2-18 years
Abetalipoproteinemia Chronic infections Chronic infections
Acrodermatitis enteropathica Post-infectious diarrhea Post-infectious diarrhea
Congenital chloridorrhea Coeliac disease Coeliac disease
Congenital sodiorrhea Chronic non-specific Irritable bowel disease
Short bowel syndrome diarrhea Lactose intolerance
Congenital lactase deficiency Food allergy Inflammatory bowel
Disaccharidase deficiency Cystic fibrosis diseases
Food allergy Autoimmune enteropathy Tumours
Glucose-galactose
malabsorption
Hirschsprung’s disease
IPEX
Malrotation
Congenital microvillous atrophy
Lymphangectasia
Biliary acids defect
Tufting enteropathy
Chronic intestinal
pseudoobstruction
 Modalities of beginning

Abrupt (e.g. infection)

Gradual
 Family history
•Coeliac disease

•Cystic fibrosis

•Atopy

•IBD

•Autoimmunity/immunodeficiency
 Growth
Very important the help from growth charts

Toddler’s diarrhea (chronic non specific diarrhea)

•No failure to thrive

•Most common cause between two and four years of age
•Intermittent and self limited
•3-6 stool day
•Not formed
•Mucous and undigested food particles
•No pain, no distension, no vomiting
•No effect on weight and on nutritional status
 Associated symptoms

•Vomiting

•Fever

•Abdominal pain

•Anorexia

•Recurrent infections
 Dietary history

Age of introduction of:

•Cow’s milk proteins

•Gluten
 Stool characteristics
•Undigested food particles

•Mucus

•Blood

•Steatorrhea

•Offensive smell

•Watery diarrhoea
 Physical examination

•Weight and height for age

•BMI

•Wasting

•Abdominal distension

•Tenderness

•Abdominal mass

•Perianal area (erythema, fissures, fistulas)

•Other organs affected (e.g. skin, respiratory…)

 Investigations

•Feces

•Blood

•Imaging

•Endoscopy & Pathology

 Blood tests

•Blood count

•Inflammatory parameters (ferritin, C

protein, ESR)

•Nutritional status (iron, transferrin,

folate,…)

•Coeliac disease serology

 Serological test for celiac disease
and new ESPGHAN guidelines

•Anti-gliadin and anti-deamidated gliadin

antibodies
•Anti tissue transglutaminase antibodies
•Antiendomysium antibodies

Biopsy may be avoided if:

•High anti-TG2 titres (>10x)
•EMA positivity
•HLA DQ2/8
•Symptoms disappearing on GFD
 Child / Adolescent with Symptoms suggestive of CD

Anti-TG2 IgA & total IgA*

Anti-TG2 Anti-TG2 Not CD

positive negative

Consider further diagnostic

Transfer to Paediatric GI testing if:
Paed. Gi discusses with family the 2 diagnostic pathways IgA deficiency
and consequences considering patient’s history & Age: < 2 years
anti-TG2 titers History: - low gluten intake
- drug pretreatment
- severe symptoms
Anti-TG2 >10 x normal Anti-TG2 <10 x normal - associated diseases

EMA & HLA DQ8/DQ2 Not OEGD & biopsies

available

EMA pos EMA pos EMA neg EMA neg Marsh 0 -1 Marsh 2 or 3
HLA pos HLA neg HLA neg HLA pos

CD+ Unclear case CD+

Consider:
Consider Consider
false positive serology
false neg. false pos.
false negative biopsy
GFD HLA test, anti-TG2
or potential CD GFD
& F/u Consider & F/u
Extended evaluation of
biopsies
HLA/;serology/biopsies
* Or specific IgG based tests
 Asymptomatic person at genetic risk for CD
explain implication of positive test result(s) and get consent for testing

HLA DQ2 / DQ8 (+/- TG2)

HLA positive HLA negative No CD,

DQ2 and/or DQ8 DQ2 and DQ8 no riks for CD

Consider retesting in
TG2 & total IgA*
intervals or if symptomatic

Titer > 3 x normal Titer < 3 x normal TG2 Negative Not CD

EMA

Consider:
OEGD & Biopsies EMA positive EMA negative
False negative results,
from Bulbus & 4 x pars descendens,
proper histological work up exclude IgA deficiency
and history of low gluten
intake or drugs

Marsh 2 or 3 Marsh 0 or 1

x
CD+ Unclear case Consider:
F/u on normal diet Consider: Transient / false positive Anti-TG2
false pos serology, false neg F/u on normal diet with further
x serological testing
GFD & F/u biopsy or potential CD
* Or specific IgG based tests
 Investigations on feces
•Electrolytes and pH

•Reducing substances

•Fat (steatocrit)

•Elastase

•Alpha 1 antitripsin

•Calprotectin/lactoferrin

•Laxatives

•Microbiology

•Gut hormones
 If feces are liquid
Na+ and K + on the liquid part

Osmotic gap = 290 – 2 (Na + + K +)

>125 mOsm/Kg = osmotic

< 50 mOsm/Kg = secretive
 Approach to secretory diarrhoea
(watery diarrhea with no or minimum
osmotic gap)
•Salmonella, Campylobacter, Shigella, E Coli
toxins
•Rotavirus

More rare causes

•Microvillous atrophy (small intestinal biopsy)

•Rare tumors (gastrin, VIP, calcitonin)
 Approach to osmotic diarrhoea and
malabsorptive syndromes

•pH and reducing substances

•Breath test (lactose for lactose intolerance, lactulose for

small bowel overgrowth)

•Sweat test (cystic fibrosis)

•Immunological tests (Ig, lymphocyte subsets)

•Small intestinal biopsy

 Imaging
• Barium follow
through
• TAC
• MRI
• Ultrasound
• Scintigraphy
(leukocytes, albumin,
RBC)
 Approach to inflammatory diarrhea

•Inflammatory parameters

•Calprotectin

•ECP

•Intestinal permeability

•Upper tract and lower tract endoscopy & biopsies

 Combined use of non-invasive tests

• Positive fecal calprotectin, • Negative fecal

ultrasound, and calprotectin, ultrasound,
ASCA/pANCA antibodies and ASCA/pANCA
antibodies
3.5 %

99.7 %

• Probability of having IBD if • Probability of not having

all tests positive IBD if all tests negative

Berni Canani R. et al JPGN 2005

 Protein losing enteropathy

•Lymphangectasia

•Infections

•Allergic gastroenteropathy

•IBD

•Congenital disorders of glicosylation

•Constrictive pericarditis & congestive heart failure

 Protein losing enteropathy

•Diarrhoea

•Edema

•Pleural and pericardial effusions

•Serum levels of albumin, alpha 1 antirypsin, fibrinogen, transferrin

•Malabsorption of fat soluble vitamins

•Hypogammaglobulinemia

•Lymphopenia and altered CMI

Classification of congenital diarrhea

Berni Canani R et al, J Pediatr Gastroenterol Nutr 2010; 50: 360-6

Molecular basis of defects of digestion, absorption
and transport of nutrients and electrolytes

Berni Canani et al, JPGN 2010; 50: 360

 Congenital Chloride Losing Diarrhea

CLD (CLD-OMIM 214700) is a congenital disorder

characterised by a defect of intestinal chloride
absorption due to mutations in the SLC26A3/DRA
gene.

Complications
- Severe dehydration
- Intestinal pseudobstruction (surgical interventions)
- Mental retardation
- Renal impairment
- Scarce quality of life
 Genetic aspects of CLD
About 50 mutation has been identified on the gene of
CLD.
All these mutations could be classified in 4 type:
a) Missence
b) Del/Ins
c) Splicing 8

d) Nonsense

2 2 2 2 2 2 2 22
1 1
Butyrrate reduces ion fecal losses

Cl- Na+

79

25
151
100

Placebo Butirrato

Data are expressed as mmol/L

Molecular basis of defects of enterocyte
differentiation and polarization

Berni Canani et al, JPGN 2010; 50: 360

Microvillous congenital atrophy
PAS staining
Microvillous congenital atrophy
Electron microscopy
Molecular basis of defects of enteroendocrine cells
differentiation

Berni Canani et al, JPGN 2010; 50: 360

Molecular basis of defects of modulation of
intestinal immune response

Berni Canani et al, JPGN 2010; 50: 360

Algorhytm for the differential diagnosis of
severe diarrhea with neonatal onset

From Goulet, 2012

Microvillous Inclusion Disease

TOTAL PARENTERAL NUTRITION

Tufting Enteropaty
• Recurrent sepsis
• PN associated liver disease
• Loss of central vascular access

Enteric Anendocrinosis

INTESTINAL TRANSPLANTATION
 TPN vs. INTESTINAL TRANSPLANTATION

Option Disease Survival (%)

1y 4y

TPN 94 80

Intestinal Tx

Intestine 70 47

Intestine+Liver 62 40

Multivisceral 45 40

Modified by SS Kaufman, JB Atkinson, A Bianchi, OJ Goulet. Pediatr Transplantation 2001; 5:80-87

 B

Before treatment 4 years of follow-up

L Bndl, T Togerson, L Perroni et al. J Pediatr 2005: 147:256-59

BONE MARROW ALLOGENIC TRANSPLANTATION
IN IPEX SYNDROME

Aarati Rao, Naynesh Kamani, Alexandra Filipovich . Blood 2007;109:383-85

 Conclusions

Chronic diarrhea may occur in many diseases including a

variety of infectious and immunological conditions

Great progress recently made in the understanding of

disease mechanisms at molecular level

Rare syndromes of intractable diarrhea have provided

important insights into gut physiology and immunology

All these new information have opened the way to more

efficient treatment for both common and rare conditions